DE2810974A1 - A SALT OF 1,3-BIS- (2-CARBOXYCHROMON-5-YLOXY) -PROPAN-2-OL AND ITS USE - Google Patents

Description

PATENT LAWYERS

Dlpl.-lng. P. WIRTH ■ Dr. V. SCHMIED-KOWARZIK DIpl.-lng. G. DANNENBERG Dr. P. WEINHOLD Dr. D. GUDEL

335024 SIEGFRIEDSTRASSE 8

TELEPHONE: C0893 ^^^ _{8000 MDNC} HEN 40

S K / SK

Fisons Limited,

Fison House, 9 Grosvenor Street

London / England

A salt of 1,3-bis (2-carboxychromon-5-yloxy) propan-2-ol and its use

The present invention relates to new compounds and mixtures and to processes for their preparation and use.

Various antihistamines have been used in the palüative treatment of allergic diseases is used. However, in most cases the antihistamines were systemic, e.g. administered as elixirs, tablets, capsules, etc. Most antihistamines also have undesirable side effects, e.g. a sedative effect, which makes its use in high doses not recommended, and when activities such as driving a car, should be undertaken.

Furthermore, disodium cromoglycate is used to treat allergic diseases and especially asthma and allergic rhinitis, has been proposed. In contrast to the antihistamines

Disodium cromoglycate is used prophylactically and morden u »is generally not recommended for use in a healing sense, i.e. during a bout of allergy.

It has now been found that mixtures of disodium cromoglycate with certain antihistamines or salts of 1,3-bis- (2-carboxychromon-5-yl-axy) -propan-2-ol with these antihistamines have the advantage that they have the advantage in comparison with the respective antihistamines when used alone or in comparison to disodium cromoglycate when used alone or in comparison to other mixtures, both palliative and prophylactic act and are even more effective in that they have fewer side effects, in lower doses and directly on the spot the allergy can be used, that they have a longer lasting effect, are more stable or other desirable Properties show up when used at certain nasal or ocular allergic manifestations are tested.

The present invention thus provides a salt of 1,3-bis- (2-carboxychromon-5-yloxy) -propan-2-ol with a basic compound with antihistamine hL receptor antagonist properties that contains a 6-membered heterocyclic nitrogen ring.

The basic compound with antihistamine-hL receptor antagonist properties can be, for example, trimeprazine, cyproheptadine, pheniramine, mepyramine, chlorpheniarmine, bromopheniramine, dimethindene, carbinoxamine, tripelennamine or, preferably, triprolidine. According to the invention the salt is at least about 1%, preferably at least 4% _t Gew./Vol. soluble in water.

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The salt can be obtained by a metathatic method such as reaction a suitable salt, such as the sodium salt, of 1,3-bis- (2-carboxychromon-5-yloxy) -propan-2-ol with a corresponding "salt, e.g. the hydrochloric", of the antihistamine will. The salt is, however, preferably by reacting the free acid, 1,3-bis- (3-carboxychromon-5-yloxy) -propan-2-ol, with the incendiary histamine free base, produced as such a process does not provide any inorganic salt as a by-product. The reaction can be carried out in a solvent which is inert under the reaction conditions be performed. The solvent used is preferably one in which the desired salt is soluble, e.g. water or an alkanal such as ethanol. The desired salt can be isolated and, for example, by crystallization or freeze drying getting cleaned.

According to the invention, an undissolved salt, e.g. one in practically dry form, is thus made available, or such a salt mixed with insufficient liquid, e.g. water, that it is not completely dissolved.

The salt can optionally together with one or more other salts of 1,3-bis- (2-carboxychromon-5-yloxy) -propan-2-ol, in particular the disodium salt thereof can be used.

According to the invention, a pharmaceutical mixture is also made available which consists of

(a) the free acid 1,3-bis- (2-carboxychromon-5 = yloxy) -propan-2-ol and / or one or more pharmaceutically acceptable salts thereof (hereinafter collectively as the "active ingredient" designated) in combination with

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(b) one or more antinine is camouflaged with HL -receptoantagonist properties and a 6-membered heterocyclic nitrogen ring, optionally in salt form. At least part of the free acid (a) can also be used as a salt of the base (b) (or a part thereof) are present.

According to the invention, the disodium salt of 1,3-bis- (2-carboxychromon-5-yloxy) -propan-2-ol, commonly referred to as disodium cromoglycate or cromolyn sodium, or

the corresponding acid
a salt / with a basic compound with antihistamine-H ,. Receptor antagonist properties and a 6-membered heterocyclic nitrogen ring used as the active ingredient.

Any of the antihistamines or described above are suitable a pharmaceutically acceptable salt thereof, such as the hydrochloride, Tartrate or maleate.

The ratio of active ingredient to antihistamine in the preparation varies with the particular active ingredient and the antihistamine used as well as the particular Ztueck for which the Preparation is intended. If the active ingredient itself is a salt of 1,3-bis- (2-carboxychromon-5-yloxy) -propan-2-ol with an antihistamine, it may be necessary to add little or no "free" antihistamine (i.e. basicBs Antihistamine itself or a different salt of antihistamine than with 1,3-bis- (2-carboxychromon-5-yloxy) -propan-2-ol) to use.

According to the invention, the preparation preferably contains only one active one Ingredient and only one antihistamine.

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An appropriate daily dose of the active ingredient for the for most purposes is between 1-100 mg, preferably 1-20 mg, (measured as disodium cromoglycate).

The appropriate daily antihistamine dose will vary with the one used Antihistamines in the following areas:

Cyproheptadine (as hydrochloride) 0.1-40

Trimeprazine (as tartrate) 0.1-40

Pheniramine (as maleate) 0.1-50

Mepyramine (as maleate) 0.1-100

Chlorpheniramine (as maleate) 0.1-20

Bromopheniramine (as maleate) 0.1-8

Dimethindine (as maleate) 0.1-6

Carbinoxamine (as maleate) 0.1-8

Tripelennamine (as hydrochloride) 0.1-100

Triprolidines (as hydrochloride), 0.1-7.5

A preferred daily antihistamine dose is between 0.1-5 mg, preferably 0.5-2 mg.

The preparation can be administered in divided doses 1 to 6 times, preferably 2 to 4 times, per day. 3ede üasis can be one or comprise several dosage units.

The specific proportions of a particular active ingredient and a particular antihistamine in each preparation according to the invention can be calculated from the above daily doses. According to the invention, a preparation with 1000-0.2 parts by weight is preferred 40-0.5 parts by weight of active ingredient (measured as disodium cromoglycate) per part by weight of antihistamine is preferred. Particularly A preparation with disodium cromoglycate and triprolidine in a weight ratio of about 20: 1 is preferred.

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The present invention also provides a method of treatment of the eyes, nose or skin in the case of an allergic disease, e.g. allergic rhinitis, whereby a salt and / or a mixture according to the invention for the patient suffering from the disease, e.g., a human. It is preferably administered through the nose.

The present invention further comprises a method of treatment of diseases of the eyes, nose or skin with an allergic component, e.g. allergic rhinitis, whereby one after the other or at the same time an active ingredient and an antihistamine with H. Receptor antagonist properties and a 6-membered heterocyclic Nitrogen ring administered and / or administered to the patient, e.g. a human.

Diseases of the external eye, in which the invention according to Procedures that can be used include Vernalkerafcoconjunctivitis, among others and marginal corneal ulceration or infiltration. Other diseases in which the process according to the invention May be applied include the effects of hay fever on the eyes, furthermore "allergic eyes", where the allergen is known or unknown, and spring / summer conjunctivitis. This last term refers to allergic disorders of the eyes that occur in spring and summer and in which one external allergen plays a role. "Irritable eyes" or "non-specific conjunctivitis", herpes simplex keratitis and conjunctivitis can be named as waitere disorders of the eyes, Herpes zoster keratitis and conjunctivitis, adenovirus infections, phlyctenular conjunctivitis, rejection of

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Corneal grafts, trachoma, and anterior uveitis Drug sensitivity.

Diseases of the nose worth mentioning include seasonal ones Rhinitis, e.g. hay fever, perennial rhinitis, nasal polyps and allergic manifestations of the nasopharynx.

Treatable dermatoses include those of the skin mast cells and / or antibody / antigen reactions, including eczema, especially atopic eczema, efflorescences caused by drugs Psoriasis, dermatitis herpetiformis, pemphigus and chronic skin ulcers, especially those in tropical humans Climates.

With sequential or simultaneous administration of the active ingredient and antihistamine are those in With respect to the mixtures described proportions and doses of active ingredient and antihistamine used. Preferred the administration of the active ingredient and antihistamine will be within about 10 minutes of each other.

The present invention therefore also provides a pharmaceutical one Pack of at least one dose of the active ingredient and at least one dose of the antihistamine. The doses are preferred Single doses and are arranged in the pack in a specific order together with printed instructions, to describe and facilitate proper intake, e.g. a dose of the active ingredient before a dose of the antihistamine. The package is preferably a sealed package

from a tube, box or card in which the cans are packed »The cans are particularly

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moderate for administration in the nose, e.g. as spray formulations for spraying into the nose, and contain the doses of active beatand part and antihistamine preferably in the above for the The proportions referred to in the preparations.

To produce suitable preparations, the salt, the active ingredient and the antihistamine are separated or mixed with an organic or inorganic, pharmaceutically acceptable auxiliary or diluent processed.

Preparations which are intended for administration in the eyes or nose are preferred, e.g. aqueous solutions with, for example, up to 10% by weight of the salt or mixture according to the invention. The preparations can also contain one or more preservatives, for example benzylconium chloride and / or phenylethyl alcohol. The preservative can contain up to 2.0 % w / v. and can be, for example, about 0.002-0.05 % w / v. Benzylconium chloride and / or about 0.1-1.0 % Gem./UoI. Phenylethyl alcohol or etuia 0.0005-0.005 % phenylmercuric nitrate or about 0.005-0.05 % thiomersal or about 0.2-1.0 % chlorobutole. The preparation can also contain a mold release agent, such as disodium edetate, which in etu / a 0.005-0.2 % Geui./Vol. anu / esend can be. The pH of the preparation can be controlled by using one or more buffers with te In, such as monosodium phosphate or disodium phosphate. The pH of the preparation can be adjusted in order to be compatible with physiological solutions and / or to improve the solubility of the constituents or to increase the stability of the preparation. The preparation can also be used as a means for

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-ir '-

Increase in its viscosity, e.g. contain certain cellulose derivatives or a polyvinyl alcohol.

The preparations to be administered into the eyes or into the nose are preferably isotonic.

According to the invention, however, powder preparations are also used for administration created in the nose, the preferably fine particles of antihistamine and / or the salt of 1,3-bis- (2-carboxychromon-5-yloxy) -propan-2-ol include.

The active ingredient and antihistamine can optionally in a specific form, e.g. with an average hatch diameter less than 10 microns.

The following examples illustrate the present invention, without restricting them.

Example 1

Chlorpheniramine salt of 1,3-bis (2-carboxychromon-5-ylaxy) propan-2-ol

3.7 parts of 1- (p-chlorophenyl) -1- (2-pyridyl) -3-N, N-dimethylpropylamine maleate were dissolved in water, made basic with 10% NaOH, extracted into ether and dried (Na ₉ SO .). The drying agent and ether were removed, then water and then 2.3 parts of 1,3-bis (2-carboxychromon-5-yloxy) propan-2-ol were added. This mixture was stirred for 2 hours, washed with ether, and the traces of ether were removed before the product was isolated from the aqueous solution by freeze-drying. Analysis for C ₂₃ H ₁₆ O _11. (C _1ß H _ig ClN ₂ ) .8H ₂ O calc .: C 60.5 H 6.5 N 5.1 %
found i C 60.0 H 5.9 N 4.9 %

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Example 2

Triprolidine salt of 1,3-bis (2-carboxychromon-5-yloxy) propan-2-ol

1.2 g of trans-2- ^ 3- (i-pyrrolidinyl) -1-p-tolypropenyl7-pyridine hydrochloride are dissolved in 50 ecm of water and made basic with 10% NaOH. The free base was extracted into ether and dried over magnesium sulfate. After filtering and evaporation of the ether, the free base remained, with a slight excess (0.9 g) of 1,3-bis- (2-carboxychromon-5-yloxy) -propan-2-ol and 20 ecm Water added. After stirring for half an hour, the insoluble materials were filtered off and the salt was isolated from the filtrate by freeze-drying. The salt was crystallized from acetone; F. undetermined - darkening and decomposition above 200 C. Analysis for ^C ₂ 3 ^H 16 ° 11 '^ ^C 19 ^H 22 ^N 2 ^ 2 * ¹ 1/2 H 0 calc .: C 69.1 H 6.1 N 5 , 3 %
found: C 69.1 H 6.2 N 5.3 %

Example 3

Triprolidine hydrochloride BP 1.0 g

Dinatrium cromoglycate BP 20.0 g

Benzalkonium chloride solution USP (50 % volume / volume) 0.31 ecm disodium edetate 0.2 g

least. Water to 1000 ecm

1 g triprolidine hydrochloride in 500 ecm of an aqueous solution Solution with 20 g disodium cromoglycate and 0.2 g disodium edetate content solved. The benzalkonium chloride u / urde in a further 300 ecm Dissolved water and this solution became disodium cromoglycate solution added. The entire solution was brought to 1000 ecm with more water and sterile filtered. The preparation was made in colored 15 ccm bottles filled with a device for Administration of measured doses of the liquid in spray form

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-M- were provided. "^ '

B is ρ ie 1 4

The preparation of Example 3 was in double-blind experiments with a 2 ^ aqueous solution of disodium cromoglycate and compared to a placebo in 16 patients suffering from allergic rhinitis. The patients listed diary cards which was expressed which of the preparations used they preferred. The analysis of the cards showed a higher preference for the preparation of Example 3 in comparison to the 2-strength aqueous Disodium cromoglycate solution and an extremely distinct preference for the preparation of Example 3 compared to the placebo.

Example 5

Triprolidine hydrochloride B.P 1, Q g

Disodium Cromoglycate B.P. 20.0 g

Disodium edeate B.P. 0.2 g

Benzoalkonium Chloride Solution USP,

50 % w / v 0.4 ecm

Phenylethyl alcohol BPC (1963) 4.2 g

least. Water to 1000.0 ecm

The Benzoalkomiumchloridlösung was with stirring in 300 ecm least. Dissolved water and then added the phenylethyl alcohol and dissolved it with stirring. The disodium edetate and triprolidine hydrochloride were distilled in another 500 ecm. Dissolved water, then the disodium crompglycate was added and dissolved. the the two solutions were mixed together and brought to the specified volume with water. This final solution became sterile filtered and aeeptically into sterile 10 cc polythene dropper bottles filled.

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Claims (8)

Patent claims
1.- Medicinal product containing (a) the free acid 1,3-bis- (2-carboxychromon-5-yloxy) -propan-2-ol and / or one or more pharmaceutically acceptable salts same in combination with (b) one or more antihistamines with H ₁ receptor antagonist properties and a 6-membered heterocyclic nitrogen ring. 2.- Medicament according to claim 1, containing disodium cromoglycate and trimeprazine, cyproheptadine, pheniramine, mepyramine, Chlorpheniramine, Brompheniramine, Dimethindene, Carbinoxamine, Tripelennamines, triprolidines and / or a pharmaceutically acceptable salt thereof and optionally customary carriers and Auxiliary materials. 3.- Medicament according to claim 1 and 2, characterized in that there are 1000-0.2 parts by weight, preferably 40-0.5 parts by weight, active ingredient (a) (measured as disodium cromoglycate) per GeiD.-part contains antihistamine. 4. Medicinal product according to claim 1, characterized in that it disodium crorooglycate and triprolidine in a weight ratio of 20: 1. 5, .- A salt of 1,3-bis- (2-carboxychromon-5-yloxy) -propan-2-ol with a basic compound with antihistamine-H, - receptor antagonist properties and a 6-membered nitrogen heterocyclic ring. 809838/0854 6.- Salt according to claim 5, characterized in that the antihistamine Trimeprazine, Cyproheptadine, Pheniramine, Mepyramine, Chlorpheniramine, Brompheniramine, Dimethindena, Carbinoxamine, Tri-pelennamine or Triprolidine is. 7.- Salt according to claim 5 and 6, characterized in that it is at least 1 % Gem./UoI. is soluble in water. 8. Chlorpheniramine or triprolidine salt of 1,3-bis- (2-carboxyd-tomon-5-yloxy) -propan-2-ol. The patent attorney: